Zonisamide is known as 1,2-benzisoxazole-3-methanesulfonamide or 3-(sulfamoylmethyl)-1,2-benzisoxazole and has anti-convulsant as well as anti-neurotic effects. It is marketed as an anti-epileptic drug (ZONEGRAN™).
The synthesis of zonisamide has been achieved by several routes, most of which begin by the conversion of 4-hydroxycoumarin into 1,2-benzisoxazole-3-acetic acid.

A variety of bases have been used in this reaction including sodium methoxide (generated in situ from sodium metal and methanol; T. Posner, Chem. Ber., 42, 1909, 2523), pyridine (Mustafa et al., Tetrahedron, 19, 1963, 1831), sodium acetate (Casini et al., J. Heterocyclic Chem., 1965, 385), alkali carbonates and aliphatic amines (United States Patent Application Publication No. US 2002/0183525 A1 and International Patent Application Publication No. WO 02/0705495 A14).
Two routes have been utilized to convert the 1,2-benzisoxazole-3-acetic acid intermediate into zonisamide. Scheme 2 depicts the initial route for its preparation by a bromination, decarboxylation and nucleophilic substitution sequence to give sodium 1,2-benzisoxazole-3-methanesulfonate (Gianella et al., Chimie Therapeutique, 7(2), 1972, 127; and Uno et al., J. Med Chem., 22(2), 1979, 180). This process provides zonisamide in ca. 44% overall yield.

Disadvantages of this process include the fact that the 1,2-benzisoxazole-3-methylbromide intermediate is a strong lachrymator and therefore it is undesirable to handle, especially on scale-up. Also, this intermediate is not very crystalline and tends to separate as an oil before solidifying thereby leading to difficulties with respect to isolation and purification.
Scheme 3 shows the second route by forming sodium 1,2-benzisoxazole-3-methanesulfonate via sulfonization of 1,2-benzisoxazole-3-acetic acid to 1,2-benzisoxazole-3-methanesulfonic acid (1).

Originally the chlorosulfonization was carried out using excess chlorosulfonic acid as a solvent (H. Uno and M. Kurokawa, Chem. Pharm. Bull, 26(11), 1978, 3498). Besides undesired ecological and safety issues that the extremely corrosive chlorosulfonic acid poses, disulfonization occurs. The removal of disulfonated product needs additional purification steps which results in loss of material and costs time, solvent and labour, etc. Later it was discovered that the use of 1,4-dioxane moderates the reactivity of chlorosulfonic acid thereby minimizing concomitant side reactions (U.S. Pat. No. 4,172,896). However, to achieve this, the reaction was carried out in 1,2-dichloroethane, which is a cancer suspect agent. This solvent poses other safety and environmental problems due to its flammability and effects on the ozone layer, respectively.
International Patent Application Publication No. WO 03/020708 A1 discloses the chlorination of sodium 1,2-benzisoxazole-3-methanesulfonate with a very large excess of phosphorous oxychloride (POCl3) to form 1,2-benzisoxazole-3-methanesulfonyl chloride (2) which is isolated and subsequently converted to zonisamide by treatment with ammonia gas (Scheme 4).

The disadvantage of this process is that the very large excess of POCl3 (8.1 mol equivalents) must be removed before isolation of 1,2-benzisoxazole-3-methanesulfonyl chloride (2) and subsequent conversion to zonisamide. Direct chlorination of 1,2-benzisoxazole-3-methanesulfonic acid (1) into 1,2-benzisoxazole-3-methanesulfonyl chloride (2) is not described in WO 03/020708. In fact, WO 03/020708 teaches that since 1,2-benzisoxazole-3-methanesulfonic acid (1) is a more hygroscopic compound than its alkaline or earth alkaline salts, it is recommended to isolate the product as a salt rather than the free sulfonic acid. Further, it is taught in WO 03/020708 that due to differences in their solubilities, it is preferable to convert the 1,2-benzisoxazole-3-methanesulfonic acid (1) into its salts for easier separation from the reaction mixture. WO 03/020708 also discloses a 1,2-benzisoxazole-3-methansulfonic acid monohydrate Form I having a water content of about 7.6% (measured by Karl Fischer titration). A 1,2-benzisoxazole-3-methanesulfonic acid (1) having a lower water content of 2.8% (measured by Karl Fischer titration) was obtained from the monohydrate but only after drying under very harsh conditions (drying for two days at 60° C. and for approximately 16 hours at 100° C.), and no further details about the compound are provided in WO 03/020708.
In Japanese unexamined (Kokai) Patent Application No. JP53077057 A2, there is mention of converting a 3-methanesulfonic acid of the general formula (VII)
directly into a methanesulfonic acid halide of the general formula (II)
using a halogenating agent, wherein X is a hydrogen atom or a 5-or 6-position halogen atom and Y indicates a halogen atom, but no further details about the 3-methanesulfonic acid (VII) have been given.
International Patent Application Publication No. WO 03/072552 A1 discloses the conversion of sodium 1,2-benzisoxazole-3-methanesulfonate into 1,2-benzisoxazole-3-methanesulfonyl chloride (2) using thionyl chloride and catalytic amounts of N,N-dimethylformamide (DMF). Although the conversion of 1,2-benzisoxazole-3-methanesulfonic acid (1) to the corresponding 1,2-benzisoxazole-3-methanesulfonyl chloride (2) is generally mentioned in this application, experimental details have only been given for the conversion of the sodium 1,2-benzisoxazole-3-methanesulfonate and, again, large excesses of highly corrosive chlorinating agents were used.
Clearly, an industrial process overcoming the deficiencies of the prior art processes, which would provide zonisamide in a high-yield, cost-effective, environmentally friendlier and safe manner was required.
None of the prior art has characterized the existence of any crystalline forms of anhydrous 1,2-benzisoxazole-3-methanesulfonic acid. There is a continuing need to investigate crystalline forms of 1,2-benzisoxazole-3-methanesulfonic acid which can provide useful intermediates for zonisamide synthesis.